The current study shows a net beneficial short-term effect of anodal tDCS applied over the left LTA on tinnitus intensity in 7 out of 20 patients (“positive responder” rate 35%) and extends previous reports by suggesting unexpected longer-lasting effects of a single tDCS session. There was no difference in the TQ and BDI scores but the study was neither designed nor powered for that purpose. The decrease of TQ scores over time may reflect a so-called “Hawthorne effect” [3
], i.e., a nonspecific improvement due to the patient’s involvement into the study and the care devoted to follow their level of well-being.
Two key differences with previous tDCS studies [9
] were the experimental design and the electrode montage. First, the current experiment assumed a double-blind, placebo-controlled, and cross-over design with a long washout period (2 weeks). This temporal aspect is especially important since the recent history of cortical excitability can shape (and even reverse) the direction of excitability changes induced by tDCS or rTMS, this phenomenon is known as homeostatic plasticity or metaplasticity [40
]. The second key difference with previous studies, in which the two electrodes were of the same size, is that we positioned a medium (35 cm2
) electrode over the left LTA and a larger (50 cm2
) electrode over the right laterofrontal scalp. Recent tDCS experiments have demonstrated that the excitability of a cortical area under a large electrode remains unchanged, ensuring that this large electrode could be considered as a real “neutral” reference electrode [26
]. Using a smaller electrode targeting the cortical area of interest and a large reference electrode helps to disambiguate the interpretation of previous tDCS studies in which a combined effect from both “active” electrodes with opposite polarities could not be ruled out. Another way to avoid this ambiguity is to use an extracephalic reference electrode, which seems to be a safe alternative [35
]. In the current experiment, the effects observed on tinnitus intensity may be chiefly driven by the DC stimulation of the left LTA; however, a significant contribution of the right frontal cognitive and limbic areas involved the emotional aspects of tinnitus [31
] can not be ruled out.
Both our responder rate (35% of the patients were “positive responders” to anodal tDCS) and effect size were comparable to those reported in previous rTMS [19
] and tDCS studies [9
]. Whereas relatively low, these responder rate and effect size still compare favorably with the lower rate of success of other therapeutic approaches. Moreover, it should be acknowledged that the therapeutic trials designed to modulate tinnitus with noninvasive transcranial brain stimulations are still in their infancy and that the optimal parameters (target area, intensity, duration, etc.) remain to be settled before launching large randomized control trials. Despite the current lack of such trial, some patient’s characteristics seem to predict a positive response to rTMS, such as tinnitus duration and normal hearing [18
], whereas age, gender, and tinnitus duration, type and laterality are not predictive for tDCS [37
Whereas a significant beneficial effect was observed exclusively for anodal tDCS, it is, however, striking to compare the stability of the variance under sham tDCS with the dynamical evolution of the variances after both anodal and cathodal tDCS (Fig. ). Two hypotheses could explain this observation. The first one is that patients became aware of the real/sham nature of the stimulations. In order to avoid drawing their attention on this aspect, we kept talking with them during stimulation. We did not ask specifically what their guess was; therefore, this possibility cannot be formally excluded. However, this is unlikely for several reasons. First, the stimulation parameters used are considered as “classical” in tDCS experiments and have been proven safe for patient’s blinding, although a significant proportion of healthy volunteers may formulate a correct guess at 1 mA [1
]. Second, during sham tDCS, the Eldith DC-Stimulator®
delivered brief and ineffective current pulses inducing a similar itching sensation that improves the blinding procedure. Third, the order of the stimulations was balanced across patients and sessions, which decreases the likelihood of unblinding all the patients. Fourth, the behavioral data were collected in a double-blind fashion. Finally, after sham tDCS, 4 of 20 patients reported short-lasting effects and 3 longer-lasting effects, suggesting they did not guess the sham nature of that stimulation. Thus, it is unlikely that the differential temporal evolution of the variance between sham and real tDCS could be explained by an unblinding of the patients.
The second hypothesis to explain this increasing variance over time solely after real but not sham tDCS is that both anodal and cathodal tDCS interacted with the left LTA activity and triggered changes in tinnitus perception/discomfort which built up over at least 1 hour, but with divergent effects (favorable or unfavorable) in different patients. At the group level, in addition to an increase of variance over time suggesting an ongoing dynamical phenomenon, anodal tDCS resulted in a net favorable effect, whereas cathodal tDCS did not. Besides the “canonical” effects on M1 excitability in humans [27
], anodal and cathodal tDCS may both have interfered with an ongoing state of abnormal excitability such as observed in tinnitus patients [31
]. This may be in line with the recent observation of large-scale network abnormalities as revealed by functional connectivity in tinnitus patients [36
]. Given the fact that several patients also reported additional changes in their tinnitus features (pitch, loudness, laterality) after real tDCS, one could hypothesize that anodal and cathodal tDCS perturbed a maladaptive equilibrium state and opened the door for plastic changes to develop, some patients taking advantage and experiencing an improvement, while others reported a worsening or useless changes in tinnitus features. The reason why tDCS triggers beneficial changes in some patients and detrimental in others remains an open question; reminiscent of the issue why some patients respond to rTMS or tDCS and others do not. This could be related to the clinical history and tinnitus features [18
], to the particular excitability of network reorganization (more or less “limbic” or “auditory”) [31
], the recent history of the LTA or connected areas excitability changes (homeostatic plasticity) [40
], or to their genetic background such as the polymorphism of the brain-derived neurotrophic factor [4
If real tDCS triggered spontaneous plastic changes by disrupting an ongoing state of abnormal excitability, this could also potentially explain the unexpected long-term effects on tinnitus spontaneously reported by our patients. Recent studies with repeated rTMS sessions have demonstrated a remarkably high success rate with long-term benefits [16
]. It is worth noting that long-lasting beneficial effects on tinnitus have been induced by repeated sessions of either low-frequency (“inhibitory”) rTMS or high-frequency (“excitatory”) rTMS in a study with a parallel group design [13
], suggesting that both low- and high-frequency rTMS could trigger plastic changes in tinnitus patients, just as we observed with a single session of anodal or cathodal tDCS.
It has been suggested that rTMS might exert a multimodal effect on tinnitus: directly on brain excitability and indirectly through acoustic stimuli and peripheral nerves stimulation [19
]; however, the involvement of peripheral nerve stimulation is debated [33
]. Transcranial direct current stimulation is less likely to benefit from such a potential multimodal effect since it does not deliver acoustic stimulation and since the itching sensation driven by DC stimulation of the scalp nerves rapidly fades. On the one hand, this may lessen the therapeutic potential of tDCS compared to rTMS. On the other hand, the conclusions from tDCS studies may be less contaminated by poorer sham conditions or multimodal effects.